tbuckley/cabot-search huggingface dataset:
Comprehensive genomic analysis of early and late-onset hepatocellular carcinoma.
Authors: Yang Shao, Xin Chen, Jiaohui Pang, Yaru Zhang, Qiuxiang Ou, Jiani Yin, Xue Wu
Journal: Journal of Clinical Oncology (2022)

e16186 Background: Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer and is a leading cause of cancer-related death worldwide. HCC is highly therapy-resistant, and biomarker-driven therapies are emerging as important treatment options. Risk factors have been implied to distinguish early and late-onset patients. A high prevalence of non-cirrhotic HCC attributed to hepatitis B virus infection was found in young Asian patients. In late-onset patients, genetic aberrations accumulated with age in liver cirrhosis and other chronic liver diseases could provide the basis of tumorigenesis. Thus, diverse genomic alteration modes may underlie HCC of different onset ages, but the analysis is lacking. This study aims to explore genomic distinctions underlying early and late-onset HCC, thus facilitating personalized biomarker-driven treatments. Methods: The plasma and tumor samples from 222 Chinese HCCs underwent genomic profiling with hybridization capture-based targeted next-generation sequencing. The patients were categorized into early (male &lt; 40 years or female &lt; 50 years) or late (male ≥ 40 years or female ≥ 50 years) onset in accordance with the American Association for the Study of Liver Diseases guideline. We compared the clinical and molecular characteristics and explored differences between the early and late-onset cohorts. Results: The late-onset cohort accounts for 83.3% (185/222) of all HCC cases, and its male incidence rate is significantly higher than that of early-onset (88.6% vs 56.8%, p&lt; 0.0001). More younger cases have a family history of HCC (21.6% vs 14.6%). The mean somatic alteration numbers per patient are comparable between early and late-onset (8.30 vs 9.92). While TP53, TERT, and MCL1 are the most frequently mutated genes in both cohorts, we identified eight genes with significantly higher mutation frequencies in early-onset. OncoKB Levels 1 to 4 actionable alterations are present in 48.7% and 44.3% of younger and older patients, respectively, whereas the early-onset cohort has a significant enrichment of actionable MDM2 alterations (10.8% vs 1.1%, p= 0.0078). The prevalence of DNA Damage Response and Repair (DDR) gene mutations (35.1% vs 48.6%) and tumor mutation burden (TMB, mean: 4.17 muts/Mb vs 8.11 muts/Mb) are elevated in older patients. Notably, individuals harboring DDR mutations are associated with higher TMB in late-onset (mean TMB in DDR-mutated: 10.44 vs DDR- wildtype: 5.90, p= 0.0016) but not early-onset (mean TMB in DDR-mutated: 3.47 vs DDR- wildtype: 4.54, p= 0.280). Conclusions: Tumors from early and late-onset HCC demonstrated differences in genes and other biomarkers relevant to cancer biology and response to therapy. Specifically, DDR-mutated patients in the late-onset cohort are associated with higher TMB and may benefit from combining targeted and immunotherapy. Future studies are warranted to examine the response to biomarker-driven treatment strategies.
INSP-16. Focused ultrasound-mediated blood-brain barrier disruption for the treatment of pediatric high-grade glioma
Authors: Dannis van Vuurden, Mario Ries
Journal: Neuro-Oncology (2022)

Abstract Pediatric patients with high-grade glioma (HGG), such as glioblastoma (GBM) and H3K27M-altered diffuse midline glioma (DMG) suffer from a dismal prognosis and a poor quality of life. So far, no therapeutic strategy has resulted in significant long-term survival benefit for these patients. Drug therapies have largely failed due to inadequate drug delivery to the brain as a result of the blood-brain barrier, preventing most drugs from entering the brain. Intrinsic and acquired tumor heterogeneity, with drug-resistant tumor cell subpopulations add to the therapeutic failure. Furthermore, these tumors evade the immune system by creating a highly tumor-promoting and immunosuppressive tumor immune microenvironment, which is composed of microglia and tumor-associated macrophages. Recently, microbubble-assisted, focused ultrasound-mediated blood-brain barrier disruption (FUS-BBBD) has emerged as a promising and clinically available technology to circumvent part of these problems. FUS-BBBD allows improved delivery of therapeutics (chemotherapy, small molecules, monoclonal antibodies, immunotherapies) to the brain. The technology is emerging both in preclinical and clinical pediatric neuro-oncology research, with invasive and minimally invasive clinical FUS-BBBD systems available for early phase clinical trials. How the right drugs in the optimal combination can be delivered with the best timing (pharmacokinetics) via FUS-BBBD has yet to be ascertained and is subject of in vitro and in vivo drug studies. Combining FUS-BBBD with compounds targeting microglia and tumor-associated macrophages potentially reverts the ‘immuno-cold’ tumor immune micro-environment towards an ‘immuno-hot’ state and might enhance systemic immunotherapies such as immune checkpoint inhibitor and CAR-T cell approaches. Furthermore, recent preclinical research evidenced that FUS-BBBD is able to enhance liquid biopsies by increasing the concentration of circulating biomarkers in blood. It could therefore be used for longitudinal monitoring of site-specific chemoresistance development during therapy. This presentation will provide an overview on preclinical and clinical developments in the field of FUS-BBBD-enhanced drug delivery, immune modulation and liquid biopsies. International collaboration in (pre)clinical studies with FUS-BBBD is needed to bring the field forward.
Efficacy and safety of pembrolizumab in combination with anlotinib in the treatment of refractory or recurrent high-grade serous ovarian cancer: A phase 2 nonrandomized clinical trial.
Authors: Man Jiang, Tianjun Li, Guanqun Wang, Xiaochun Zhang
Journal: Journal of Clinical Oncology (2022)

5543 Background: Anlotinib, an oral multi-targeted receptor tyrosine kinase inhibitor (TKI), exhibits good safety and efficacy in many advanced refractory solid tumors. Previous studies have indicated that anlotinib has synergistic effects with anti–programmed death-1 antibodies via modulation of the tumor microenvironment. Our study aims to examine the efficacy and safety of anlotinib-pembrolizumab combination therapy as a treatment for refractory or recurrent High-Grade Serous Ovarian Cancer. Methods: Patients with refractory or recurrent High-Grade Serous Ovarian Cancer received pembrolizumab (200 mg, intravenously over 60 minutes, once every 3 weeks) plus anlotinib (12 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) therapy or pembrolizumab (200 mg, intravenously over 60 minutes, once every 3 weeks) monotherapy, respectively. Primary end points were progression-free survival (PFS) and overall survival (OS). The relationships of potential biomarkers with clinical efficacy were also evaluated. Results: A total of 33 patients were enrolled, with 15 participants received the anlotinib-pembrolizumab combination regime and 18 with pembrolizumab monotherapy, respectively. Grade 3 treatment-related adverse events (TRAEs) were recorded in 3 participants (20%) receive the combination treatment and 3 (16.7%) in the pembrolizumab monotherpay group, respectively. The PFS were 13.0 months and 8.0 months to anlotinib-pembrolizumab combination regime and pembrolizumab mono-treatment, respectively. And the OS of the two groups were equal as 31 months. In the anlotinib-pembrolizumab combination treatment group, patients with ARID1A mutation indicated a significantly survival benefit compared patient with the wide type (PFS: 12.5 VS. 7.0, P = 0.004 ). Conclusions: The anlotinib-pembrolizumab combination showed promising efficacy and favorable safety as treatment for refractory or recurrent High-Grade Serous Ovarian Cancer. The ARID1A are potential biomarkers for predicting the efficacy of this novel regimen.
IL‐31 levels correlate with pruritus in patients with cholestatic and metabolic liver diseases and is farnesoid X receptor responsive in NASH
Authors: Jun Xu, Ya Wang, Mina Khoshdeli, Matt Peach, Jen‐Chieh Chuang, Julie Lin, Wen‐Wei Tsai, Sangeetha Mahadevan, Wesley Minto, Lauri Diehl, Ruchi Gupta, Michael Trauner, Keyur Patel, Mazen Noureddin, Kris V. Kowdley, Aliya Gulamhusein, Christopher L. Bowlus, Ryan S. Huss, Robert P. Myers, Chuhan Chung, Andrew N. Billin
Journal: Hepatology (2022)

Pruritus is associated with multiple liver diseases, particularly those with cholestasis, but the mechanism remains incompletely understood. Our aim was to evaluate serum IL-31 as a putative biomarker of pruritus in clinical trials of an farnesoid X receptor (FXR) agonist, cilofexor, in patients with NASH, primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC).
MEDB-82. Exploring cell-cell communication networks in medulloblastoma using single-cell genomics
Authors: Lisa Gabler, Johannes Gojo, Kyle S Smith, Laure Bihannic, Mariella G Filbin, Paul A Northcott, Walter Berger, Volker Hovestadt
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is a high-risk embryonal brain tumor arising in the cerebellum. Genomic profiling has revealed a striking molecular heterogeneity between medulloblastoma patients, yet treatment regimens are mostly uniform. Many children with medulloblastoma die from their disease and surviving patients often face severe long-term side effects, highlighting an urgent need for more effective treatment options. We and others have recently identified pronounced intra-tumoral heterogeneity and defined cellular hierarchies within medulloblastoma tumors. The functional role of these cellular hierarchies remains unknown. We now hypothesize the existence of an inter-cellular communication network that is maintained by receptor/ligand interactions. To test our hypothesis, we use our medulloblastoma single-cell RNA sequencing dataset of 25 patients, as well as bulk RNA sequencing, DNA methylation array, and genome sequencing data across molecular subtypes. Single-cell RNA sequencing data are analyzed to dissect cell compartments characterized by high expression of potentially oncogenic receptors and their respective ligands. Consequently, cell type-specific roles in auto- or paracrine signal transduction within the cellular community are explored. We further investigate downstream oncogenic signaling pathways by approximating transcription factor activity and explore genetic and epigenetic activation mechanisms by matched genome sequencing and DNA methylation profiling, respectively. Our findings will be applied to deconvolute bulk RNA sequencing data, thus identifying therapeutically relevant signaling networks in larger cohorts of medulloblastoma patients. Eventually, candidate targets will be validated on patient-derived cell models and xenografts by overexpression and inhibition studies. Together, here we aim at identifying tumor-driving receptor/ligand interactions in medulloblastoma, with the goal to define targets susceptible to precision oncology approaches.
Influence of factors on systolic blood pressure in patients with hypertension identified during screening
Authors: ZH Bekbergenova, G Derbissalina, A Umbetzhanova, SH Batarbekova, A Masharipova, G Mauletbayeva, D Akhmetova, E Kelimberdiyeva
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Main funding source(s): - Background / Introduction. Hypertension is one of the most common causes of myocardial infarction and stroke in the Republic of Kazakhstan (RK). Blood pressure (BP) is an easily measured indicator of hypertension. Purpose To assess the effect of various factors on systolic blood pressure (SBP) in patients with hypertension identified at screening. Methods A survey of 354 patients with hypertension identified at screening was carried out and the influence of various factors on SBP was assessed. Results The average age of patients is 54 years [Q1-Q3: 50-54], of which 36.2% are men, 63.8% are women. Middle systolic blood pressure is 140 [Q1-Q3: 130-140] mm Hg. Most of the respondents have varying degrees of obesity. The average body mass index is 31.86 [Q1-Q3: 29.4-31.86]. The average waist is 95 [Q1-Q3: 92-95]. Mean values of total cholesterol. 5.8 [Q1-Q3: 5.6-5.8]. With an increase in age by 1 full years, an increase in SBP by 0.148 mm.Hg. should be expected. In accordance with the coefficient of determination R2 in the resulting model, 0.56% of the factors influencing the value of SBP were taken into account. With an increase in body mass index by 1, a decrease in SBP by 0.059 mm Hg should be expected. In accordance with the coefficient of determination R2 in the resulting model, 0.04% of the factors influencing the SBP were taken into account. With an increase in the waist by 1 cm, an increase in SBP by 0.059 mm Hg should be expected. In accordance with the coefficient of determination R2 in the resulting model, 0.09% of the factors influencing the SBP were taken into account. With an increase in total cholesterol by 1 mmol/l. an increase in SBP by 24.466 mm Hg should be expected. In accordance with the coefficient of determination R2, the resulting model took into account 34.27% of the factors affecting the SBP. The effect of total cholesterol on SBP was statistically significant (p = 0.001) (methods used: Kruskal-Wallis test). Conclusion (s) Thus, the effect of total cholesterol on SBP is statistically significant (p = 0.001). With an increase in total cholesterol by 1 mmol/l. an increase in SBP by 24.466 mm Hg should be expected.
Prevalence of underlying cirrhosis etiologies in hepatocellular carcinoma patients of Hispanic versus non-Hispanic ethnicity.
Authors: Jeremy Chang, Veeral Ajmera, Kathryn J Fowler, Stephanie Ting, Pablo Tamayo, Adam Burgoyne
Journal: Journal of Clinical Oncology (2022)

e16163 Background: While the incidence and rates of mortality are in decline for the vast majority of cancers, those of hepatocellular carcinoma (HCC) continue to increase. Forecasts from the Surveillance, Epidemiology, and End Results (SEER) database suggest that the Hispanic population will have the highest incidence rate of HCC in the United States by the end of this decade. As a result, further studies are needed to identify specific risk factors for the development of HCC in this ethnic group. Methods: This was a retrospective, single center study conducted in Southern California to identify the prevalence of underlying cirrhosis etiologies in HCC patients of Hispanic versus non-Hispanic ethnicity. Causes of cirrhosis included nonalcoholic fatty liver disease (NAFLD), viral hepatitis, alcohol, and other chronic liver disease. The designation of NAFLD cirrhosis was assigned to patients in whom there was an exclusion of viral hepatitis B, viral hepatitis C, significant alcohol consumption, other etiology of chronic liver disease, and who had the presence of fatty liver on imaging or were diagnosed with cirrhosis with a concomitant metabolic risk factor (diabetes mellitus, hypertension, hyperlipidemia, or obesity). Results: A total of 165 patients were included in this study. There were 57 patients of Hispanic ethnicity and 108 patients of non-Hispanic ethnicity. No significant differences in age or gender were found between the two groups. When analyzing the prevalence of cirrhosis etiologies, 17 patients (29.8%) of Hispanic background were found to have underlying NAFLD cirrhosis compared to 10 patients (9.3%) of non-Hispanic background (p = 0.001). In contrast, 67 patients (62%) in the non-Hispanic group had diagnoses of cirrhosis associated with viral hepatitis B or C compared to 22 patients (38.6%) in the Hispanic group (p = 0.005). There was no significant difference in the prevalence of alcoholic cirrhosis (24.6% vs 13%, p = 0.08), cirrhosis due to other chronic liver disease (1.8% vs 2.8%, p = 1), or HCC without cirrhosis (5.3% vs 13%, p = 0.178) between Hispanic and non-Hispanic patients, respectively (Table). Conclusions: There were significantly higher rates of NAFLD cirrhosis identified in HCC patients of Hispanic ethnicity compared to those of non-Hispanic ethnicity. With the continually rising incidence rate of HCC in this patient group, it is important for providers to be aware of this association so that appropriate surveillance and prevention strategies may be pursued.[Table: see text]
RARE-11. 60 years single centre experience of craniopharyngioma management
Authors: Beryl Rodrigues, Jenny Adamski, Martin English, Helen Curry, Guirish Solanki, Andrew Peet, John Apps
Journal: Neuro-Oncology (2022)

Abstract Adamantinomatous craniopharyngiomas are challenging intracranial tumours associated with significant morbidity. Management includes surgery and radiotherapy, with a shift towards more conservative surgery in recent years, aimed at preserving hypothalamic function. The West Midlands Regional Children’s Tumour Registry collects detailed clinical, pathological and follow up information on patients treated within the region from 1957. 52 cases (26 male, 26 female) of craniopharyngioma treated at Birmingham Children’s Hospital 1957-2018, were identified, with further clinical details obtained from patient records, where available. Visual symptoms were the commonest presenting feature (63%), followed by headache (48%), vomiting (31%), neurological symptoms (31%) and features of endocrine disorders (21%) with a median symptom duration of 6 months (range &amp;lt;1-24). Initial management was with gross total resection (GTR) in 14 patients, subtotal resection in 22 patients and subtotal resection with adjuvant radiotherapy in seven patients. Two patients received radiotherapy without resection, and five patients underwent cystic drainage procedures alone. Two patients initially underwent shunt insertion alone, but received radiotherapy at progression. 30 (58%) patients underwent relapse/progression, with a median time to progression of 1.2 years (range 0.2-6.3). 15 had further surgery. Radiotherapy was used in 14/15 patients who had not previously received radiotherapy, with the other undergoing a GTR. To date 10 patients have died, nine from tumour related reasons and one from pulmonary embolism. Where data was available at follow up, all patients had at least one endocrinopathy, with 38/45 patients having diabetes insipidus. Hypothalamic obesity was identified in 14/36 (39%) patients with sufficient records, with this more common in those undergoing GTR (7/9 (78%)) compared to other surgical procedures (7/27)(26%)(p&amp;lt;0.05). Three patients have developed neurovascular complications and three fatty liver disease. This experience is consistent with the literature and supports the increasing usage of hypothalamic sparing surgical management.
TBIO-11. The glutamine transporter and candidate diagnostic and therapeutic target SLC1A5 is associated with subtype-specific metabolic phenotypes and tumor prognosis in pediatric brain cancers
Authors: Adam Kraya, Run Jin, Chao Zhao, Ariana Familiar, Kathryn Wellen, Adam Resnick, Ali Nabavizadeh
Journal: Neuro-Oncology (2022)

Abstract Glutamine transporters play an important role in supporting increased tumor nutritional demands relative to non-cancerous cells, often through overexpression of the solute carrier (SLC) family of membrane transporters. Preclinical studies in adult cancers demonstrate that targeting glutamine addiction via SLC1A5 inhibition results in growth-inhibitory and tumoricidal effects. Given their relatively higher expression in cancer versus normal brain tissue, SLC transporters represent compelling targets for molecularly-targeted radiation and application of available prognostic amino-acid PET imaging probes. However, the role of SLC transporters in pediatric brain cancers has yet to be investigated. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes in ensemble survival models (Reactome: R-HSA-352230), we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Through transcriptome-based consensus clustering, we found that supratentorial, RELA fusion-positive ependymomas and sonic hedgehog-activated medulloblastomas were over-represented among clusters expressing higher levels of SLC1A5 (p = 3.38e-7 and p = 2.18-26, respectively). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 9.8e-4 and p = 0.032) and shorter PFS in LGG (p = 0.022). Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. Our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain cancers that warrant further investigation for molecularly-targeted treatment and amino-acid PET imaging.
Supportive care (SC) utilization for patients with locally advanced pancreatic cancer: Review of the National Cancer Data Base (2004-2018).
Authors: Christopher G Cann, Chan Shen, Michael Brian LaPelusa, Rajiv Agarwal, Dana Backlund Cardin, Cathy Eng
Journal: Journal of Clinical Oncology (2022)

4154 Background: Pancreatic cancer is a formidable malignancy, with an estimated 62,000 new cases in 2022 and approximately 50,000 deaths. Five-year overall survival remains low at 11%; 14.4% for locally advanced disease. Nearly one-third of newly diagnosed patients (pts) present with locally advanced pancreatic cancer (LAPC) and only a minority of pts (&lt;25%) are eligible for surgical resection. Given the significant morbidity and mortality associated with LAPC, timely integration of SC into the treatment care plan is vital. Methods: Pts diagnosed with Stage II-III LAPC (2004-2018) recorded in the National Cancer Data Base were included, stratified by stage and use of SC (defined as procedures or therapy provided for palliative intent symptom control) from time of diagnosis throughout the disease trajectory. Analyses included tumor characteristics, demographics, and socioeconomic parameters. Multivariate logistic regressions were performed on three sets of data: Stage II, Stage III, and Stage II/III combined. Results: 158,340 pts were included in the cohort [stage II (70.6%); stage III (29.4%)]. Only a minority of pts (2.9%) received SC treatment despite &gt; 65% of pts receiving care at an academic program; 95% living in or near a metro area, and nearly 60% living &lt; 20 miles of their primary treatment center (p &lt;0.001). Medicare (58%) and private insurance (32.8%) was consistent across both stages and SC use. The table depicts selected significant factors and the respective adjusted odds of receiving SC from the three logistic regressions. Conclusions: Our analysis demonstrates the underutilization of SC in LAPC population over the past decade and potential specific demographic/social areas of unmet need. Future work should focus on practice patterns across cancer centers and the significant impact SC has on both survival and quality of life outcomes for LAPC pts. SC should be an integral component incorporated early on in the care of pancreatic cancer regardless of stage. [Table: see text]